Process for making 2-hydroxyquinoline-4-carboxylic acids

ABSTRACT

Process for the preparation of 2-hydroxyquinoline-4-carboxylic acids in which 2-hydroxy-4-halogeno-methyl-quinoline is oxidized with a controlled excess of alkaline hydrogen peroxide.

llnited States Patent 51 3,691,171 Boosen [451 Sept. 12, 1972 PROCESS FOR MAKING 2- [56] References Cited HYDROXYQUINOLINE- l- UNIT D TAT A NTCARBOXYLIC ACIDS 3 391 146 7 19 18 s G :f TE S 260 28 Invento K l J fBwsen a Neuvevine a r l O rey 7 Switzerland OTHER PUBLICATIONS [73]Assignee: Lonza Ltd., Basle, Switzerland R empp Chemie g 6 g B d P- 22Filed: May 26,1 970 4742 1966) [21] Appl. No; 40,696 PrimaryExaminer-Donald G. Daus Attorney-Henry T. Burke, Robert Scobey, RobertS. Dunham, P. E. Henninger, Lester W. Clark, Gerald 1 ForeignApplication Priority Data w. Griffin, Thomas F. Moran, R. Bradlee Boa]and May 29,1969 Switzerland ..8l09/69 Chmmpherc Dunham 52 us.c|...,...26o/2s7 R, 260/283 SY, 260/289 R [57] ABSTRACT [51] Int. Cl...C07d 33/48 Process for the preparation of 2-hydroxyquinoline-4- [58]carboxylic acids in which 2-hydroxy-4-halogeno- Field of Search";..260/287-R, 640

methyl-quinoline is oxidized with a controlled excess of alkalinehydrogen peroxide.

6 Claims, N0 Drawings PROCESS Fox MAKING 4-CARBOXYLIC ACIDSBACKGROUND'OF INVENTION 1 The S-methyl substituted and 8-chlorinesubstituted Z-hydroxyquinoline-4 carboxylic acids have known utility asintermediates'for the productionof pharmaceutically useful compounds,especially local anesthetics. They have been prepared by variousmethods. For-example, 2 -hydroxyquinoline-4-carboxylic acid has beenobtained from isatin, which is inturn prepared-by. oxidizing indigo withnitric or chromic hydride at atemperature of from 210C. to 220C. at apressure'of about fourteen atmospheres, absolute. The yields obtainedare about 65 to 72 percent, and these add. ln the procedure isatin isreacted with acetic an- Z-HYDROXYQUINOLINE- While the 4-chloromethylcompound is the preferred ly determined by simple tests of the peroxidecontent of a the reaction'mixture with elapsed time. Usually thereaction is complete in from about 4 to 8 hours. After the reaction iscomplete, the free quinolinecarboxylic acid is liberated byacidification with nonare comparable 'with yieldsobtained inthepreparation of homologs and analogs by'other procedures.

THEINVENTIQN. I It has now been found thatQ-hydroxyquinoIine-4-carboxylic acids ,canbe prepared in high yield and p'urity by, a muchless rigorous. method which does require-high temperatures andpressures.

'{ln'accor'dance vwith the invention the desired result is obtained byreacting the starting compound with a controlled excess of alkalinehydrogen peroxide to effect oxidation tothe final product. The selected2-hydroxy- 4-halogenomethyl quinoline is reacted with hydrogen peroxideat a mole ratio of from 1:10 to 1:20 between the starting material andthe hydrogen peroxide in an aqueous solution containing an alkali metalhydroxide at a mole ratio offr'orn 1:6 to 1:15 between the startingmaterial and the hydroxide. The temperature of the i not reaction isfrom about'35C. to 70C.The product ob- -tained is an alkali metal saltof the 2-hydroxyquinoline- 4-carboxylic acid,; and the free acid isobtained by acidifying with a non-oxidizing acid, suitably a mineralacid such as hydrochloric, sulfuric or phosphoric acid.

For the separation the acidity of the solution is brought .to a pH offrom about 1 to 4 to precipitate the acid.

The reaction takes place, as described above, in the presence of. anexcess of hydrogen peroxide and alkaline agent, e.g., alkali hydroxide.However, care must be taken that not too' large an excess is employed,otherwise there is the danger that strong hydrolysis will take place andinstead of the desired final product, a 2-hydroxy-4-hydroxymethylquinoline is obtained. For this reason care mustbe-exercised that the amount of hydrogen peroxide and alkaline agentemployed do not vary appreciably from the range set forth above. In factit is preferred that the mole ratio of starting material to hydrogenperoxide is from 1:15 to 1:20 and to alkali hydroxide is 1:10 to 1:12.

The preferred procedure is to feed the aqueous solution of alkali metalhydroxide first, heat it to a tern erature preferably about 50C. and70C. and to simultaneously add the hydrogen peroxide and the startingcompound in the desired quantities at a rate so as to maintain thetemperature in the range 50C. to 70C.

Although appreciable variation in the concentration of hydrogen peroxideand alkali metal hydroxide can be tolerated, so long as the mole ratiosare as described above, it is preferred that the concentration of usedhydrogen eroxide solution be from about to 35 percent, suitably percent,and the used alkali hydroxide solutionbe from about 9 to l6 percent.

oxidizing mineral acids, such as hydrochloric, sulphuric, orphosphoricacid. The acidity, as described above, is preferably broughtto a pH of l to 4. The

quinolinecarboxylic acid is then separated, preferably by filtration attemperatures below room temperature,

washed and dried. v

The product is preferably dried in a vacuum (approximately 10 to 25 mmHg). lf drying temperatures of 50+60C. are used,the2-hydroxyquinoline-4-carboxylic acid is obtained'with 1 mol water ofcrystallization. If the temperatures are 130C. to 150C. the acid isobtained free of water in the anhydrous form. 1

The 2 hydroxyquinoline-4-carboxylic acids prepare may optionally bearany substituent on the quinoline nucleus, particularly alkyl or halogensubstituents at the 8-position.

The 2-hydroxy-4 halogenmethylquinolines are easily obtained and-with ahigh yield from the corresponding anilides of gamma-halogenacetoneaceticacids. These in turn can be obtained, by chlorination of diketenes andsubsequent reaction of the gammahalogenacetonacetic acid products withthe suitable aromatic amines and further closing of the ring with thehelp of concentrated sulphuric acid.

The following non-limiting examples are given by wayof illustrationonly.

EXAMPLE 1 Twenty-four g. of NaOH and 150 ml water were placed into a2-liter flask withfour orifices, and heated to 50C.; ml 30 percenthydrogen peroxide and 9.7 g. Z-hydroxy-4-chloromethylquinoline wereadded simultaneously during an interval of 20 minutes and thetemperature was maintained at 50 C. for 8 hours. The aqueous solutionwas then filtered, acidified with 200 ml aqueous hydrochloric acid(1:1), cooled at 10C. and the desired product recovered as a precipitateby filtration and dried in a vacuum (20 mm Hg) at 150C. After thematerial was recrystallized from glacial acetic acid or ethanol, 7.6 g.(approximately 80 percent of the theoretical yield) of2-hydroxyquinoline-4-carboxylic acid were obtained. The melting pointwas 335-340 C., the purity, from potentiometric titration, was 99.9percent.

EXAMPLE 2 Thirty-four g. KOl-l and 200 ml water were placed in theflask, as in Example 1, and ml H 0 (30 percent) were added,simultaneously with 19.4 g. 2-

hydroxy-4-chloromethylquinoline, during an interval of 30 minutes, at50C. The temperature was kept at 50C. for 8 hours. After filtration theproduct was acidified with aqueous hydrochloric acid 1:1) to a pH of 2.The mixture was cooled to C. the 2-hydroxyquinoline-4-carboxylic acidwas separated, dried in vacuum at 150C. and recrystallized as describedabove. The result was 15.0 g. or approximately 84 percentof thetheoretical yield of hydroxyquinoline carboxylic acid with a meltingpoint of 335-340C.

EXAMPLE 3 2-hydroxy-4-bromomethylquinoline was oxidized, as described inExample 1, and then treated further as described above. Afterrecrystallization from glacial acetic acid a yield of-68 percent of2hydroxyquinoline- 4-carboxylic acid was obtained.

EXAMPLE 4 22.5 (0.1 mol) gamma-chloroacetonaceto-Z- toluidine wereheated to 90C. to 100C. for 20 minutes in 30 ml concentrated sulphuricacid. After cooling the solution was poured into 1 liter water and theprecipitate recovered by filtration and washed. The result of thisreaction was 17.5 g. 2-hydroxy-4- chloromethyl-8-methylquinoline (yieldequal to 84.6 percent of the theoretical value). The melting point wasbetween 218C. and 220C. This 2-hydroxy-4- chloromethyl-8-methylquinolinewas oxidized in a manner analogous to that of Example 1. After furthertreatment and recrystallization from glacial acetic acid there wereobtained 11.1 g. (corresponding to 54.7 percent of the theoreticalvalue) of 2-hydroxy-8- methylquinoline-4-carboxylic acid with a meltingpoint of3 12C. to 315C. The purity was 99.8 percent.

EXAMPLE 5 Eighty-seven g. (0.35 mol)gammachloroacetonacetic-2-chloroanilide were treated with 450 mlconcentrated sulphuric acid at 20C. during 16 hours. After pouring intowater the precipitate was recovered by filtration and washed. Theresulting product was 57 g. (corresponding to 72.3 percent) of2-hydroxy-4-chloromethyl-8-chloroquinoline with a melting point of 187C.to 188C. (recrystallized from glacial acetic acid). The oxidation waseffected in accordance with Example 1. The results was 2-hydroxy-8-chloroquinoline-4-carboxylic acid with a yield of 85.5 percent. Themelting point was between 330C. and 332C. and the purity was 99 percent.

What is claimed is:

1. A process for the preparation of Z-hydroxy-quinoline-4-carboxylicacids which comprises oxidizing the corresponding2-hydroxy-4-halogenomethylquinoline by reaction with aqueous alkalinehydrogen peroxide at a temperature of from about 35C. to C. utilizing amole ratio of starting material to hydrogen peroxide of from about 1:10to 1:20, and starting material to alkali hydroxide of 1:6 to 1:15 andthereafter acidifying the mixture with a strong non-oxidizing acid.

2. A process as in claim 1 wherein the temperature is from 50C. to 70C.

3. A process as in claim 1 wherein the alkaline solution is preheated toabout 35C. to 70C. and the hydrogen peroxide and startin material areadded slmu taneously at a rate to mam am the reaction tem-

2. A process as in claim 1 wherein the temperature is from 50*C. to70*C.
 3. A process as in claim 1 wherein the alkaline solution ispreheated to about 35*C. to 70*C. and the hydrogen peroxide and startingmaterial are added simultaneously at a rate to maintain the reactiontemperature at from about 35*C. to 70*C.
 4. A process as in claim 1wherein the mol ratio of starting material to alkali hydroxide is from1:10 to 1:12.
 5. A process as in claim 1 in which the concentration ofthe alkali hydroxide is from about 9 to 16 percent.
 6. A process as inclaim 1 wherein the mol ratio of starting material to hydrogen peroxideis 1:15 to 1:20.